1. Field of the Invention
The invention relates to a process for preparing cyclopropanecarboxylates of lower alcohols by esterification of the carboxylic acids with the lower alcohols.
2. Discussion of the Background
Cyclopropanecarboxylates of lower alcohols have recently achieved considerable significance as intermediates in the synthesis of pharmaceuticals and pesticides. This has partly been due to the fact that cyclopropanecarboxylic acid has more recently become readily available by oxidation of the corresponding aldehyde (see U.S. Pat. No. 5,504,245) and is being produced industrially. However, there has hitherto been no satisfactory process for preparing these esters.
The esterification of carboxylic acids with an alcohol with the liberation of water is a known reaction which leads to an equilibrium. The equilibrium is usually attained more quickly using acid catalysts. Removal of the water of reaction using an entrainer and/or use of an excess of alcohol can shift the equilibrium in the direction of ester formation. This principle is applied in the process in the Patent Specification SU 322 986, in which cyclopropanecarboxylic acid is esterified at about 80xc2x0 C. using a large excess of methanol in the presence of p-toluenesulfonic acid as catalyst, and toluene or carbon tetrachloride as entrainer for the water. However, the yield of 70% is unsatisfactory. Also, the entrainer introduces a further substance into the process.
Kohlrausch and Skrabal (Monatsh. Chem 70 [1937], 377,395) prepared methyl cyclopropanecarboxylates by esterifying the acid with methanol using concentrated sulfuric acid as catalyst. However, the resulting crude ester had to be distilled several times in order to obtain a pure product. Every additional distillation increases the cost and reduces the yield.
Folmer and Weinreb (Tetrahedron Lett. [1993] 34 (17), 2737-40) achieved relatively good yields of methyl cyclopropanecarboxylate by carrying out esterification at temperatures of from xe2x88x9278xc2x0 C. to room temperature, but the auxiliaries they used, the so-called Appel salt (4,5-dichloro-1,2,3-dithiazolium chloride) and 2,6-dimethylpyridine, are expensive and difficult to dispose of.
These and other processes described in the literature operate at temperatures below 100xc2x0 C. (e.g. Saigo, Kazihiko Saigo, Masahiro Usui, Kazumori Kikuchi, Eiichiro Shimada and Teruaki Mukayama, Bull. Chem. Soc. Jpn. [1977] 50 (7), 1863-6 at room temperature) and thus take into account the known thermal instability of cyclopropane compounds (see e.g. Hans Beyer, Lehrbuch der Organischen Chemie [Handbook of Organic Chemistry], publisher S. Hirzel, Leipzig, 15th/16th edition (1968), page 357). Most of the known processes operate with an excess of alcohol in the esterification zone. The processes have unsatisfactory yields, disadvantageously large numbers of stages and/or require auxiliaries which are expensive and difficult to dispose of.
It was therefor the object of the invention to provide a process which gives good yields, uses inexpensive auxiliaries and produces a product which can be purified in a simple manner.
This object is achieved by a process for preparing cyclopropanecarboxylates of lower alcohols by esterification of the corresponding cyclopropanecarboxylic acids with the corresponding lower alcohols in the presence of an acid catalyst, which comprises maintaining in the esterification zone a considerable stoichiometric excess of the cyclopropanecarboxylic acid with respect to the lower alcohol, keeping the temperature in the esterification zone at from 100 to 200xc2x0 C. and distilling off, from the reaction zone, the cyclopropane carboxylate together with the water of reaction and small amounts of alcohol. The process according to the invention produces high purity esters in yields of more than 90%, based on reacted cyclopropanecarboxylic acid. Surprisingly, it is not necessary to operate under gentle conditions, i.e. at temperatures  less than 100xc2x0 C. The cyclopropanecarboxylic acid, which is sensitive to thermal stress, particularly in an acid medium, is exposed to these stress conditions for considerably longer than the alcohol, which is unproblematical in this respect, as the cyclopropanecarboxylic acid is present in considerable excess. Despite this, there are no secondary reactions, and traces of decomposition products have never been found. Because of the high temperatures, excellent space-time yields are also obtained. The process can be carried out batchwise or, with particular advantage, continuously.
In the process according to the invention, the unsubstituted cyclopropanecarboxylic acid or its ring-substituted derivatives, e.g. the cyclopropanecarboxylic acids ring-substituted by 1 or 2 alkyl radicals having 1 to 4 carbon atoms, are reacted.
The cyclopropanecarboxylates of lower alcohols are useful in the synthesis of pharmaceuticals and pesticides.
Preferred lower alcohols are those whose boiling point does not differ greatly from that of water at atmospheric pressure, i.e. in the region of 100xc2x1about 40xc2x0 C. Preferred lower alcohols are alkanols having 1 to 4 carbon atoms, such as ethanol, n-propanol, i-propanol, n-butanol and, in particular, methanol.
Suitable esterification catalysts are the known acid catalysts, such as sulfuric acid; sulfonic acid group-containing ion exchange resins; sulfonic acids, such as methanesulfonic acid, higher alkanesulfonic acids, benzenesulfonic acid, p-toluenesulfonic acid and, in particular, higher alkybenzenesulfonic acids, preferably those having branched or unbranched C10- to C13-alkyl radicals. The amount of catalysts used is generally such that their proportion in the esterification zone is from 0.1 to 10 percent by weight.
The process of the invention is advantageously carried out at a temperature of from 120 to 200xc2x0 C., preferably between 130 to 150xc2x0 C. It is generally carried out at atmospheric pressure. Elevated pressure is recommended if the process is to be carried out at a temperature at which the cyclopropanecarboxylic acid is gaseous under atmospheric pressure (un-substituted cyclopropanecarboxylic acid boils at 182xc2x0 C.). Reduced pressure can be applied when a relatively high-boiling lower alcohols, such as n-propanol, is used.
An important feature of the process according to the invention is that there is a considerable stoichiometric excess of cyclopropanecarboxylic acid with respect to the lower alcohol in the esterification zone. As a rule, the cyclopropanecarboxylic acid is present in an amount of from 2 to 1000, preferably 10 to 200, times the stoichiometric quantity. When the process is carried out batchwise, the lower alcohol can, for example, be introduced gradually on its own into the initial charge of cyclopropanecarboxylic acid, or alternatively in the form of a mixture with further cyclopropanecarboxylic acid, the proportion thereof being less than that of the ester produced in the esterification zone. In both cases, the initial charge of cyclopropanecarboxylic acid is consumed at a more or less rapid rate. Lower alcohol which distills off with the water of reaction can be returned to the esterification. When the process is carried out continuously the cyclopropanecarboxylic acid is again initially charged and a mixture of cyclopropanecarboxylic acid and lower alcohol is added to it, the mixing ratio being chosen such that the amount of cyclopropanecarboxylic acid introduced corresponds to the ester which is produced in the reaction zone and distills off, so that a steady state prevails in the reaction zone. That is generally the case when the molar ratio of cyclopropanecarboxylic acid and lower alcohol, depending on the starting substances, is in the range from 1:1.20 to 1:1.02, advantageously from 1:1.10 to 1:1.05. The slight excess of lower alcohol distills off with the ester formed and the water of reaction.
The vapor mixture is condensed, and the condensate forms two phases. The upper, aqueous phase can be partially distilled to recover the lower alcohol contained therein and the resulting lower alcohol be returned to the esterification. Further distillation of the aqueous phase produces small quantities of ester which, after separation from the water which is co-distilled azeotropically, can also be returned to the esterification or can be worked up together with the lower, organic phase. The residue is waste water with few impurities, which can easily be disposed of.
The lower, organic phase is partially distilled in a similar way and thus separated from small amounts of water and lower alcohol. The residue is very pure cyclopropanecarboxylate which does not need to be distilled further for the majority of uses.
The following examples serve to illustrate in more detail the process according to the invention, but are not intended to limit its field of application as defined in the patent claims. All contents and percentages were determined by gas chromatography.